Researching COVID to enhance recovery (RECOVER) adult study protocol: Rationale, objectives and design (preprint)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged [≥]18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.

Effectiveness of Sotrovimab in Preventing COVID-19-related Hospitalizations or Deaths Among U.S. Veterans (preprint)

Background: Data on effectiveness of sotrovimab preventing COVID-19-related hospitalization or mortality, particularly after the emergence of the Omicron variant, are limited. Method: Determine the real-world clinical effectiveness of sotrovimab for prevention of 30-day COVID-19 related hospitalization or mortality using a retrospective cohort within the U.S. Department of Veterans Affairs (VA) healthcare system. Veterans aged [≥]18 years, diagnosed with COVID-19 between December 1, 2021, and April 4, 2022, were included. Sotrovimab recipients (n=2,816) were exactly matched to untreated controls (n=11,250) on date of diagnosis, vaccination status, and region. The primary outcome was COVID-19-related hospitalization or all-cause mortality within 30 days from diagnosis. Cox proportional hazards modeling estimated the hazard ratios (HR) and 95% Confidence Interval (CI) for the association between receipt of sotrovimab and outcomes. Results: During BA.1 dominance, compared to matched controls, sotrovimab-treated patients had a 70% lower risk hospitalization within 30 days or mortality (HR 0.30; 95%CI, 0.23-0.40), a 66% lower risk of 30-day hospitalization (HR 0.34; 95%CI, 0.25-0.46), and a 77% lower risk of 30-day all-cause mortality (HR 0.23; 95%CI, 0.14-0.38). During BA.2 dominance sotrovimab-treated patients had a 71% (HR .29; 95%CI, 0.08-0.98) lower risk of 30-day COVID-19-related- hospitalization, emergency, or urgent care. Limitations include confounding by indication. Conclusions: Using national real-world data from high risk and predominantly vaccinated Veterans, administration of sotrovimab, compared with no treatment, was associated with reduced risk of 30-day COVID-19-related hospitalization or all-cause mortality during the Omicron BA.1 period and reduced risk of progression to severe COVID-19 during the BA.2 dominant period.

Tixagevimab/Cilgavimab for Prevention of COVID-19 during the Omicron Surge: Retrospective Analysis of National VA Electronic Data (preprint)

Background: Little is known regarding the effectiveness of tixagevimab/cilgavimab in preventing SARS-CoV-2 infection in this population, particularly after the emergence of the Omicron variant. Objective: To determine the effectiveness of tixagevimab/cilgavimab for prevention of SARS-CoV-2 infection and severe disease among immunocompromised patients. Design: Retrospective cohort study with propensity matching and difference-in-difference analyses. Setting: U.S. Department of Veterans Affairs (VA) healthcare system. Participants: Veterans age [≥]18 years as of January 1, 2022, receiving VA healthcare. We compared a cohort of 1,848 patients treated with at least one dose of intramuscular tixagevimab/cilgavimab to matched controls selected from 251,756 patients who were on immunocompromised or otherwise at high risk for COVID-19. Patients were followed through April 30, 2022, or until death, whichever occurred earlier. Main Outcomes: Composite of SARS-CoV-2 infection, COVID-19-related hospitalization, and all-cause mortality. We used cox proportional hazards modelling to estimate the hazard ratios (HR) and 95% CI for the association between receipt of tixagevimab/cilgavimab and outcomes. Results: Most (69%) tixagevimab/cilgavimab recipients were [≥]65 years old, 92% were identified as immunocompromised in electronic data, and 73% had [≥]3 mRNA vaccine doses or two doses of Ad26.COV2. Compared to propensity-matched controls, tixagevimab/cilgavimab-treated patients had a lower incidence of the composite COVID-19 outcome (17/1733 [1.0%] vs 206/6354 [3.2%]; HR 0.31; 95%CI, 0.18-0.53), and individually SARS-CoV-2 infection (HR 0.34; 95%CI, 0.13-0.87), COVID-19 hospitalization (HR 0.13; 95%CI, 0.02-0.99), and all-cause mortality (HR 0.36; 95%CI, 0.18-0.73). Limitations: Confounding by indication and immortal time bias. Conclusions: Using national real-world data from predominantly vaccinated, immunocompromised Veterans, administration of tixagevimab/cilgavimab was associated with lower rates of SARS-CoV-2 infection, COVID-19 hospitalization, and all-cause mortality during the Omicron surge.

Analysis of severe illness after post-vaccination COVID-19 breakthrough among adults with and without HIV in the United States (preprint)

ImportanceUnderstanding the severity of post-vaccination COVID-19 breakthrough illness among people with HIV (PWH) can inform vaccine guidelines and risk-reduction recommendations. ObjectiveEstimate the rate and risk of severe breakthrough illness among vaccinated PWH and people without HIV (PWoH) who experience a breakthrough infection. Design, setting, and participantsThe Corona-Infectious-Virus Epidemiology Team (CIVET-II) collaboration consists of four US longitudinal cohorts from integrated health systems and academic centers. Adults ([≥]18 years old), in-care, fully vaccinated by June 30, 2021 with HIV, and matched PWoH (on date fully vaccinated, age group, race/ethnicity, and sex) were the source population. Those who experienced a post-vaccination SARS-CoV-2 breakthrough infection were eligible. Severe COVID-19 breakthrough illness was defined as hospitalization due to COVID-19. Discrete time proportional hazards models estimated adjusted hazard ratios (aHR) and 95% confidence intervals ([,]) of severe breakthrough illness by HIV status adjusting for demographics, COVID-19 vaccine type, and clinical factors. The proportion of patients requiring mechanical ventilation or died was compared by HIV status. ExposureHIV infection OutcomeSevere COVID-19 breakthrough illness, defined as hospitalization within 28 days after a breakthrough SARS-CoV-2 infection with a primary or secondary COVID-19 discharge diagnosis. ResultsAmong 1,241 PWH and 2,408 PWoH with breakthrough infections, the cumulative incidence of severe illness in the first 28 days was low and comparable between PWoH and PWH (7.3% vs. 6.7%, respectively, risk difference=-0.67% [-2.58%, 1.23%]). The risk of severe breakthrough illness was 59% higher in PWH with CD4 counts <350 cells/mm3 compared with PWoH (aHR=1.59 [0.99, 2.46]). In multivariable analyses among PWH, being female, older, having a cancer diagnosis, and lower CD4 count increased the risk of severe breakthrough illness, while previous COVID-19 reduced the risk. Among all patients, 10% were mechanically ventilated and 8% died, with no difference by HIV status. Conclusions and RelevanceThe risk of severe COVID-19 breakthrough illness within 28 days of a breakthrough infection was low among vaccinated PWH and PWoH. However, PWH with moderate and severe immune suppression had a higher risk of severe breakthrough infection. Recommendations for additional vaccine doses and risk-reduction strategies for PWH with moderate immune suppression may be warranted. Key PointsO_ST_ABSQuestionC_ST_ABSIn 2021, among fully vaccinated people with COVID-19 breakthrough illness, was the risk of severe illness higher in people with HIV (PWH) compared to people without HIV (PWoH)? FindingsPWH with <350 cells/mm3 have a 59% increased risk of severe breakthrough illness compared to PWoH. MeaningVaccinations effectively reduce the risk of severe COVID-19 infection in both PWH and PWoH; however, PWH having a CD4 count <350 cells/mm3 are at higher risk of severe breakthrough infection compared to PWoH. PWH with moderate immune suppression should be considered for additional vaccine dosages and other risk-reduction measures.

Baricitinib plus Standard of Care for Hospitalised Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomized, Placebo-Controlled Trial. (preprint)

ABSTRACT Background: The oral, selective Janus kinase (JAK)1/JAK2 inhibitor baricitinib demonstrated efficacy in hospitalised adults with COVID[ndash]19. This study evaluates the efficacy and safety of baricitinib in critically ill adults with COVID[ndash]19 requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Methods: COV[ndash]BARRIER was a global, phase 3, randomised, double[ndash]blind, placebo[ndash]controlled trial in patients with confirmed SARS[ndash]CoV[ndash]2 infection (ClinicalTrials.gov NCT04421027). This addendum trial added a critically ill cohort not included in the main COV[ndash]BARRIER trial. Participants on baseline IMV/ECMO were randomly assigned 1:1 to baricitinib 4[ndash]mg (n=51) or placebo (n=50) for up to 14 days in combination with standard of care (SOC). Prespecified endpoints included all[ndash]cause mortality through days 28 and 60, and number of ventilator[ndash]free days, duration of hospitalisation, and time to recovery through day 28. Efficacy and safety analyses included the intent[ndash]to[ndash]treat and safety populations, respectively. Findings: SOC included baseline systemic corticosteroid use in 86% of participants. Treatment with baricitinib significantly reduced 28[ndash]day all[ndash]cause mortality compared to placebo (39[middot]2% vs 58[middot]0%; hazard ratio [HR]=0[middot]54 [95%CI 0[middot]31[ndash]0 [middot]96]; p=0[middot]030). One additional death was prevented for every six baricitinib[ndash]treated participants. Significant reduction in 60[ndash]day mortality was also observed (45[middot]1% vs 62[middot]0%; HR=0[middot]56 [95%CI 0[middot]33[ndash]0[middot]97]; p=0[middot]027). Baricitinib[ndash]treated participants showed numerically more ventilator[ndash]free days (8.1 vs 5.5 days, p=0.21) and spent over 2 days less in the hospital than placebo[ndash]treated participants (23[middot]7 vs 26[middot]1 days, p=0[middot]050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment arms. Interpretation: In critically ill patients with COVID[ndash]19 already receiving IMV/ECMO, treatment with baricitinib as compared to placebo (in combination with SOC, including corticosteroids) showed mortality HR of 0[middot]56, corresponding to a 44% relative reduction at 60 days. This is consistent with the mortality reduction observed in less severely ill hospitalised primary COV[ndash]BARRIER study population. Funding: Eli Lilly and Company. Research in context Evidence before this study We evaluated current and prior studies assessing the efficacy and safety of interventions in patients requiring invasive mechanical ventilation (IMV) and searched current PubMed using the terms [quot]COVID[ndash]19[quot], [quot]SARS[ndash]CoV[ndash]2[quot], [quot]treatment[quot], [quot]critical illness[quot], [quot]invasive mechanical ventilation[quot], [quot]baricitinib[quot], and [quot]JAK inhibitor[quot] for articles in English, published until December 1, 2020, regardless of article type. We also reviewed the NIH and IDSA COVID[ndash]19 guidelines and reviewed similar terms on clinicaltrials.gov. When the critical illness addendum study to COV[ndash]BARRIER study was designed, there was only one open[ndash]label study of dexamethasone showing mortality benefit in hospitalised patients with COVID[ndash]19 requiring IMV. Small studies of interleukin[ndash]6 inhibitors had shown no effect and larger trials were underway. Guidelines recommended use of dexamethasone with or without remdesivir and recommended against the use of interleukin[ndash]6 inhibitors, except in a clinical trial. Overall, there were no reported double[ndash]blind, placebo[ndash]controlled phase 3 trials which included corticosteroids as part of SOC investigating the efficacy and safety of novel treatments in the NIAID[ndash]OS 7 population. Baricitinib[apos]s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID[ndash]19 given its known anti[ndash]cytokine properties and potential antiviral mechanism for targeting host proteins mediating viral endocytosis Data from the NIAID sponsored ACTT[ndash]2 trial showed that baricitinib when added to remdesivir improved time to recovery and other outcomes including mortality compared to placebo plus remdesivir. A numerically larger proportion of participants who received baricitinib plus remdesivir showed an improvement in ordinal scale compared to those who received placebo plus remdesivir at day 15 in participants requiring IMV (NIAID[ndash]OS score of 7) at baseline. We designed COV[ndash]BARRIER, a phase 3, global, double[ndash]blind, randomised, placebo[ndash]controlled trial, to evaluate the efficacy and safety of baricitinib in combination with SOC (including corticosteroids) for the treatment of hospitalised adults with COVID[ndash]19 who did not require mechanical ventilation (i.e., NIAID[ndash]OS 4[ndash]6). A significant reduction in mortality was found after 28 days between baricitinib and placebo (HR 0[middot]57, corresponding to a 43% relative reduction, p=0[middot]0018); one additional death was prevented per 20 baricitinib[ndash]treated participants. In the more severely ill NIAID[ndash]OS 6 subgroup, one additional death was prevented per nine baricitinib[ndash]treated participants (HR 0[middot]52, corresponding to a 48% relative reduction, p=0[middot]0065). We therefore implemented an addendum to the COV[ndash]BARRIER trial to evaluate the benefit/risk of baricitinib in the critically ill NIAID[ndash]OS 7 population and considered the sample size of 100 participants sufficient for this trial. Added value of this study This was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC), including antivirals, anticoagulants, and corticosteroids, in patients who were receiving IMV or extracorporeal membrane oxygenation at enrolment. This was a multinational, randomised, double[ndash]blind, placebo[ndash]controlled trial in regions with high COVID[ndash]19 hospitalisation rates. Treatment with baricitinib reduced 28[ndash]day all[ndash]cause mortality compared to placebo (HR 0[middot]54, 95% CI 0[middot]31[ndash]0[middot]96; nominal p=0[middot]030), corresponding to a 46% relative reduction, and significantly reduced 60[ndash]day all[ndash]cause mortality (HR 0[middot]56, 95% CI 0[middot]33[ndash]0[middot]97; p=0[middot]027); overall, one additional death was prevented per six baricitinib[ndash]treated participants. Numerical improvements in endpoints such as number of ventilator[ndash]free days, duration of hospitalisation, and time to recovery were demonstrated. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively. The COV[ndash]BARRIER study overall trial results plus these COV[ndash]BARRIER addendum study data in mechanically ventilated and ECMO patients provide important information in context of other large, phase 3 randomised trials in participants with invasive mechanical ventilation at baseline. The RECOVERY study reported mortality of 29[middot]3% following treatment with dexamethasone compared to 41[middot]4% for usual care (rate ratio of 0[middot]64, corresponding to a 36% relative reduction) and 49% mortality in participants who received tocilizumab compared to 51% for usual care (rate ratio of 0[middot]93, corresponding to a 7% relative reduction). The ACTT[ndash]2 study reported 28[ndash]day mortality of 23[middot]1% and 22[middot]6% in the baricitinib plus remdesivir and placebo plus remdesivir groups, respectively, in this critically ill patient population; however, the primary outcome of this trial was time to recovery, so was not powered to detect a change in mortality. Implications of all the available evidence In this phase 3 addendum trial, baricitinib given in addition to SOC (which predominantly included corticosteroids) had a significant effect on mortality reduction by 28 days in critically ill patients, an effect which was maintained by 60 days. These data were comparable with those seen in the COV[ndash]BARRIER primary study population of hospitalised patients, but which excluded patients who required IMV or extracorporeal membrane oxygenation at enrolment. These findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on the available evidence, baricitinib is a novel treatment option to decrease mortality in hospitalised, critically ill patients with COVID[ndash]19 even when started late in the disease process after steroids, mechanical ventilation, and ECMO have already been implemented.

LENZILUMAB EFFICACY AND SAFETY IN NEWLY HOSPITALIZED COVID-19 SUBJECTS: RESULTS FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL (preprint)

BACKGROUND: Severe COVID19 pneumonia results from a hyperinflammatory immune response (cytokine storm, CS), characterized by GM CSF mediated activation and trafficking of myeloid cells, leading to elevation of downstream inflammatory chemokines (MCP1, IL8, IP10), cytokines (IL6, IL1), and other markers of systemic inflammation (CRP, D dimer, ferritin). CS leads to fever, hypotension, coagulopathy, respiratory failure, ARDS, and death. Lenzilumab is a novel Humaneered anti-human GM CSF monoclonal antibody that directly binds GM CSF and prevents signaling through its receptor. The LIVE AIR Phase 3 randomized, double blind, placebo controlled trial investigated the efficacy and safety of lenzilumab to assess the potential for lenzilumab to improve the likelihood of ventilator free survival (referred to herein as survival without ventilation, SWOV), beyond standard supportive care, in hospitalized subjects with severe COVID-19. METHODS: Subjects with COVID-19 (n=520), >18 years <94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Subjects were followed through Day 28 following treatment. RESULTS: Baseline demographics were comparable between the two treatment groups: male, 64.7%; mean age, 60.5 years; mean BMI, 32.5 kg/m2; mean CRP, 98.36 mg/L; CRP was <150 mg/L in 77.9% of subjects. The most common comorbidities were obesity (55.1%), diabetes (53.4%), chronic kidney disease (14.0%), and coronary artery disease (13.6%). Subjects received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the likelihood of SWOV by 54% in the mITT population (HR: 1.54; 95% CI: 1.02 to 2.31, p=0.041) and by 90% in the ITT population (HR: 1.90; 1.02 to 3.52, nominal p=0.043) compared to placebo. SWOV also relatively improved by 92% in subjects who received both corticosteroids and remdesivir (1.92; 1.20 to 3.07, nominal p=0.0067); by 2.96-fold in subjects with CRP<150 mg/L and age <85 years (2.96; 1.63 to 5.37, nominal p=0.0003); and by 88% in subjects hospitalized <2 days prior to randomization (1.88; 1.13 to 3.12, nominal p=0.015). Survival was improved by 2.17-fold in subjects with CRP<150 mg/L and age <85 years (2.17; 1.04 to 4.54, nominal p=0.040). CONCLUSION: Lenzilumab significantly improved SWOV in hospitalized, hypoxic subjects with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Subjects with CRP<150 mg/L and age <85 years demonstrated an improvement in survival and had the greatest benefit from lenzilumab. NCT04351152

Baricitinib plus Standard of Care for Hospitalized Adults with COVID-19 (preprint)

Background: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, improved outcomes in a previous randomized controlled trial of hospitalized adults with COVID-19, in combination with remdesivir. Methods: In this phase 3, global, double-blind, randomized, placebo-controlled trial, 1525 hospitalized adults with COVID-19 receiving standard of care (SOC) were randomly assigned (1:1) to once-daily baricitinib 4-mg (N=764) or placebo (N=761) for up to 14 days. SOC included systemic corticosteroids in ~79% of participants (dexamethasone ~90%). The primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. A key secondary endpoint was all-cause mortality by day 28. Results: Overall, 27.8% of participants receiving baricitinib vs 30.5% receiving placebo progressed (primary endpoint, odds ratio 0.85, 95% CI 0.67-1.08; p=0.18). The 28-day all-cause mortality was 8.1% for baricitinib and 13.1% for placebo, corresponding to a 38.2% reduction in mortality (hazard ratio [HR] 0.57, 95% CI 0.41-0.78; nominal p=0.002); 1 additional death was prevented per 20 baricitinib-treated participants. Reduction in mortality was seen for all pre-specified subgroups of baseline severity (most pronounced for participants on high-flow oxygen/non-invasive ventilation at baseline [17.5%, baricitinib vs 29.4%, placebo; HR 0.52, 95% CI 0.33-0.80; nominal p=0.007]). The frequency of adverse events, serious adverse events, serious infections, and venous thromboembolic events was similar between groups. Conclusions: While reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (predominantly dexamethasone) significantly reduced mortality with a similar safety profile between groups of hospitalized COVID-19 participants.